Liquid Mixing System with Vertically Adjustable Mixing Element and Method of Use

ABSTRACT

A liquid mixing system includes a support housing at least partially bounding a compartment. A mount is secured to the support housing. A drive motor assembly is configured to engage a drive shaft for moving the drive shaft within the compartment of the support housing. A four bar linkage system extends between the mount and the drive motor assembly, the four bar linkage system being movable between a first position wherein the drive motor assembly is disposed at a first elevation and a second position wherein the drive motor assembly is disposed at a second elevation that is different from the first elevation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/799,580, filed Oct. 31, 2017, which claims the benefit of U.S.Provisional Application No. 62/415,949, filed Nov. 1, 2016, which areincorporated herein by specific reference.

BACKGROUND OF THE INVENTION 1. The Field of the Invention

The present invention relates to liquid mixing systems that are commonlyused as bioreactors or fermenters and have a vertically adjustablemixing element.

2. The Relevant Technology

The biopharmaceutical industry uses a broad range of liquid mixingsystems for a variety of processes such as in the preparation of mediaand buffers and in the growing of cells and microorganisms. Someconventional mixing systems, including bioreactors, comprise a flexiblebag disposed within a rigid support housing. An impeller is disposedwithin the flexible bag and is used to mix or suspend the solutionwithin the bag. In some embodiments, the impeller is mounted to thebottom of the bag and is magnetically driven. In other embodiments, theimpeller is fixed on the end of a drive shaft that projects into theflexible bag. In both embodiments, however, the impeller is designed toremain at a substantially fixed position which is optimal for mixing anarrowly defined volume of solution in the flexible bag. To enablehomogeneous mixing of larger volumes of solution, larger bags are usedthat have an impeller positioned at a location that is optimal for thatsize of bag.

In some processing procedures it can be desirable to initially mixsolutions at a low volume and then progressively increase the volume ofthe solution. For example, this is a Common procedure used withbioreactors for growing cells. The process typically entails dispensinga seed inoculum in a growth media contained within a relatively smallbag and then transferring the solution to progressively larger bagswhere additional media is added as the cells grow and multiply. Thisprocess is repeated until a final desired volume is achieved. Bytransferring the solution to different sized bags which each have acorresponding mixer, the operator can ensure homogeneous mixing of eachof the different volumes.

Although the above process of moving solutions to different sized bagsto maintain proper mixing and suspension is functional, the procedurehas some shortcomings. For example, the necessity of stepping todifferent sized bags is labor intensive, time consuming, and has highmaterial costs in that the multiple bags are discarded after use.Furthermore, transferring between different bags produces some mixingdown-time which can influence cell growth. In addition, the necessity ofshifting between bags increases the risk of contamination to thesolution and potential damage to the cells.

Accordingly, what is needed in the art are improved mixing systems thatsolve all or some of the above problems.

SUMMARY OF THE INVENTION

In a first independent aspect of the present invention, a liquid mixingsystem includes:

-   -   a support housing at least partially bounding a chamber, the        support housing having a top opening that communicates with the        compartment;    -   a mount secured to the support housing so as to span across the        top opening; and    -   a drive motor assembly secured to the mount so that the drive        motor assembly can be selectively raised and lowered between at        least two positions, the drive motor being configured to engage        a drive shaft for moving the drive shaft within the chamber of        the support housing.

In one embodiment, a four bar linkage system secures the drive motorassembly to the mount, the four bar linkage system being movable toselectively raise and lower the drive motor assembly between the atleast two positions.

In another embodiment, the four bar linkage system is movable between alowered position wherein the drive motor assembly is disposed at a firstangular orientation and an elevated raised position wherein the drivemotor assembly is disposed at a second angular orientation that isdifferent from the first angular orientation.

In another embodiment, the angular orientation of the drive motorassembly automatically changes as the four bar linkage system is movedbetween the lowered position and the raised position.

In another embodiment, the angular orientation of the drive motorassembly changes in a range between 1° and 15° and more commonly between1° and 10°, 2° and 7°, or 2° and 5° as the four bar linkage system ismoved between the lowered position and the raised position.

In another embodiment, the four bar linkage system comprises four armseach having a first end hingedly connected to the drive motor assemblyand an opposing second end hingedly connected to the mount.

In another embodiment, the invention further comprises:

-   -   a support extending between two of the four arms of the four bar        linkage system; and    -   a drive assembly extending between the mount and the support.

In another embodiment, the mount comprises:

-   -   an elongated first rail spanning across the top opening and        having opposing ends secured to the support housing;    -   an elongated second rail spanning across the top opening and        having opposing ends secured to the support housing, the second        rail being spaced apart from the first rail;    -   a brace extending between the first rail and the second rail so        as to be disposed over the top opening.

In another embodiment, the first rail and the second rail are U-shapedor arched shaped and upwardly project from the support housing.

In another embodiment, a drive assembly extends between the mount andthe four bar linkage system and controls movement of the four barlinkage system.

In another embodiment, the drive assembly comprises a hydraulic orpneumatic piston.

In another embodiment, the support housing has an annular flange thatencircles the top opening, the mount being secured on opposing sides ofthe annular flange so that the mount spans entirely across the topopening.

In another embodiment, a flexible bag is disposed within the chamber ofthe support housing, the flexible bag bounding a compartment and beingcoupled to the drive motor assembly.

In another embodiment, the flexible bag is collapsible and is comprisedof a polymeric film having a thickness in a range between 0.02 mm and 1mm with between 0.02 mm and 0.5 mm and between about 0.02 and 0.2 mmbeing more common.

In another embodiment, a drive shaft is coupled with the drive motorassembly, at least a portion of the drive shaft being disposed withinthe compartment of the flexible bag, the drive motor assembly rotatingthe drive shaft when the drive motor assembly is activated.

In another embodiment, a mixing element is disposed within thecompartment of the flexible bag and coupled with the drive shaft.

In another embodiment, the mixing element comprises an impeller.

In another embodiment, the invention further comprises:

-   -   a rotational assembly comprising an outer casing secured to the        flexible bag and a tubular hub rotatably disposed within the        outer casing, a passage extending through the tubular hub;    -   an impeller disposed within the compartment of the flexible bag;    -   a tubular member extending between the hub of the rotational        assembly and the impeller; and    -   a drive shaft engaged with the drive motor assembly and the        impeller and passing through the tubular hub and tubular member.

In a second independent aspect of the present invention, a liquid mixingsystem includes:

-   -   a support housing at least partially bounding a compartment;    -   a mount secured to the support housing;    -   a drive motor assembly configured to engage a drive shaft for        moving the drive shaft within the compartment of the support        housing; and    -   a four bar linkage system extending between the mount and the        drive motor assembly, the four bar linkage system being movable        between a first position wherein the drive motor assembly is        disposed at a first elevation and a second position wherein the        drive motor assembly is disposed at a second elevation that is        different from the first elevation.

In one embodiment, the four bar linkage system automatically changes theangular orientation of the drive motor assembly as the drive motorassembly is moved from the first elevation to the second elevation.

In another embodiment, the angular orientation of the drive motorassembly changes by at least 1° and more commonly at least 2° 3°, 4°,5°, or 6° as the drive motor assembly is moved from the first elevationto the second elevation.

In another embodiment, the four bar linkage system comprises four armseach having a first end hingedly connected to the drive motor assemblyand an opposing second end hingedly connected to the mount.

In another embodiment, the invention further comprises:

-   -   a support extending between two of the four arms of the four bar        linkage system; and    -   a drive assembly extending between the mount and the support.

In another embodiment, the drive assembly comprises a hydraulic orpneumatic piston.

In another embodiment, the mount comprises:

-   -   an elongated first rail spanning across the top opening and        having opposing ends secured to the support housing;    -   an elongated second rail spanning across the top opening and        having opposing ends secured to the support housing, the second        rail being spaced apart from the first rail;    -   a brace extending between the first rail and the second rail so        as to be disposed over the top opening.

In another embodiment, the first rail and the second rail are U-shapedor arch shaped and upwardly project from the support housing.

In another embodiment, a drive assembly extends between the brace andthe four bar linkage system and controls movement of the four barlinkage system.

In another embodiment, the drive assembly comprises a hydraulic orpneumatic piston.

In another embodiment, the support housing has an annular flange thatencircles the top opening, the mount being secured on opposing sides ofthe annular flange so that the mount spans entirely across the topopening.

In another embodiment, a container is disposed within the chamber of thesupport housing, the container bounding a compartment and being coupledto the drive motor assembly.

In another embodiment, a drive shaft is coupled with the drive motorassembly, at least a portion of the drive shaft being disposed withinthe compartment of the container, the drive motor assembly rotating thedrive shaft when the drive motor assembly is activated.

In another embodiment, a mixing element is disposed within thecompartment of the container and coupled with the drive shaft.

In another embodiment, the mixing element comprises an impeller.

In another embodiment, the invention further comprises:

-   -   a rotational assembly comprising an outer casing secured to the        container and a tubular hub rotatably disposed within the outer        casing, a passage extending through the tubular hub;    -   an impeller disposed within the compartment of the flexible bag;    -   a tubular member extending between the hub of the rotational        assembly and the impeller; and    -   a drive shaft engaged with the drive motor assembly and the        impeller and passing through the tubular hub and tubular member.

The second aspect of the invention may also include any of the features,options and possibilities set out elsewhere in this document, includingin or associated with the above first or below third aspect of theinvention.

In a third independent aspect of the present invention, a method formixing a liquid includes:

-   -   moving a mixing element disposed at a first location within a        compartment of a container so as to mix a first volume of a        liquid within the compartment;    -   adding liquid to the compartment of the container so as to form        a second volume of the liquid within the compartment;    -   moving a four bar linkage system so as to raise the mixing        element within the compartment of the container to a second        position; and    -   moving the mixing element at the second position so as to mix        the second volume of liquid within the container.

In one embodiment, moving the mixing element comprises rotating themixing element.

In another embodiment, the mixing element comprises an impeller.

In another embodiment, the step of moving the four bar linkage systemautomatically adjusts an angular orientation of the mixing element.

In another embodiment, the angular orientation of the mixing element ismoved by an angle of at least 1°, 2°, 3°, 4°, 5°, 7°, 10°, 15°, or 20°as the mixing element is moved from the first position to the secondposition.

In another embodiment, the mixing element is moved by a verticaldistance of at least or less than 5 cm, 10 cm, 20 cm, 40 cm, or 60 cm asit is moved from the first position to the second position.

In another embodiment, the invention further comprises:

-   -   a support housing at least partially bounding a compartment;    -   a mount secured to the support housing;    -   a drive motor assembly;    -   a drive shaft coupled with the drive motor assembly, the mixing        element being coupled to the drive shaft; and    -   the four bar linkage system comprising four arms each having a        first end hingedly connected to the drive motor assembly and an        opposing second end hingedly connected to the mount.

In another embodiment, the step of moving a four bar linkage systemcomprises pivoting each of the four arms.

In another embodiment, the step of moving a four bar linkage systemcomprises moving a piston extending between the mount and the four barlinkage system.

The third aspect of the invention may also include any of the features,options and possibilities set out elsewhere in this document, includingin or associated with the above first and second aspect of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention will now be discussed withreference to the appended drawings. It is appreciated that thesedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting of its scope.

FIG. 1 is a perspective view of a fluid mixing system;

FIG. 2 is a perspective view of the container assembly of the fluidmixing system shown in FIG. 1;

FIG. 3 is an exploded view of the mixing assembly shown in FIG. 2 andthe drive shaft used therewith;

FIG. 4 is a cross sectional side view of the rotational assembly of themixing assembly shown in FIG. 3;

FIG. 5 is a partially exploded front view of the mixing assembly anddrive shaft shown in FIG. 3 aligned for use with the drive motorassembly;

FIG. 6 is an enlarged top perspective view of the drive motor assemblyshown in FIG. 5 with the drive shaft coupled thereto;

FIG. 7 bottom perspective view of the drive motor assembly shown in FIG.5;

FIG. 8 is a top perspective view of the drive motor assembly, mount, andfour bar linkage system shown in FIG. 1, attached to the annular flangeof the support housing;

FIG. 9 is a side perspective view of the components in FIG. 8;

FIG. 10 is an exploded view of the four bar linkage system shown in FIG.8 and the drive motor assembly;

FIG. 11 is a right side perspective view of the four bar linkage systemcoupled to the drive motor assembly;

FIG. 12 is a left side perspective view of the four bar linkage systemcoupled to the drive motor assembly;

FIG. 13 is a left side view of the four bar linkage system holding thedrive motor assembly in a lowered position; and

FIG. 14 is a left side view of the four bar linkage system holding thedrive motor assembly in a raised position.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before describing the present disclosure in detail, it is to beunderstood that this disclosure is not limited to parameters of theparticularly exemplified systems, methods, apparatus, products,processes, compositions, and/or kits, which may, of course, vary. It isalso to be understood that the terminology used herein is only for thepurpose of describing particular embodiments of the present disclosure,and is not necessarily intended to limit the scope of the disclosure inany particular manner. Thus, while the present disclosure will bedescribed in detail with reference to specific embodiments, features,aspects, configurations, etc., the descriptions are illustrative and arenot to be construed as limiting the scope of the claimed invention.Various modifications can be made to the illustrated embodiments,features, aspects, configurations, etc. without departing from thespirit and scope of the invention as defined by the claims. Thus, whilevarious aspects and embodiments have been disclosed herein, otheraspects and embodiments are contemplated.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the present disclosure pertains. While a number ofmethods and materials similar or equivalent to those described hereincan be used in the practice of the present disclosure, only certainexemplary materials and methods are described herein.

Various aspects of the present disclosure, including devices, systems,methods, etc., may be illustrated with reference to one or moreexemplary embodiments or implementations. As used herein, the terms“embodiment,” “alternative embodiment” and/or “exemplary implementation”means “serving as an example, instance, or illustration,” and should notnecessarily be construed as preferred or advantageous over otherembodiments or implementations disclosed herein. In addition, referenceto an “implementation” of the present disclosure or invention includes aspecific reference to one or more embodiments thereof, and vice versa,and is intended to provide illustrative examples without limiting thescope of the invention, which is indicated by the appended claims ratherthan by the following description.

It will be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a “rail” includes one, two, or more rails. Similarly,reference to a plurality of referents should be interpreted ascomprising a single referent and/or a plurality of referents unless thecontent and/or context clearly dictate otherwise. Thus, reference to“rails” does not necessarily require a plurality of such rails. Instead,it will be appreciated that independent of conjugation; one or morerails are contemplated herein.

As used throughout this application the words “can” and “may” are usedin a permissive sense (i.e., meaning having the potential to), ratherthan the mandatory sense (i.e., meaning must). Additionally, the terms“including,” “having,” “involving,” “containing,” “characterized by,”variants thereof (e.g., “includes,” “has,” and “involves,” “contains,”etc.), and similar terms as used herein, including the claims, shall beinclusive and/or open-ended, shall have the same meaning as the word“comprising” and variants thereof (e.g., “comprise” and “comprises”),and do not exclude additional, un-recited elements or method steps,illustratively.

Various aspects of the present disclosure can be illustrated bydescribing components that are coupled, attached, connected, and/orjoined together. As used herein, the terms “coupled”, “attached”,“connected,” and/or “joined” are used to indicate either a directconnection between two components or, where appropriate, an indirectconnection to one another through intervening or intermediatecomponents. In contrast, when a component is referred to as being“directly coupled”, “directly attached”, “directly connected,” and/or“directly joined” to another component, no intervening elements arepresent or contemplated. Thus, as used herein, the terms “connection,”“connected,” and the like do not necessarily imply direct contactbetween the two or more elements. In addition, components that arecoupled, attached, connected, and/or joined together are not necessarily(reversibly or permanently) secured to one another. For instance,coupling, attaching, connecting, and/or joining can comprise placing,positioning, and/or disposing the components together or otherwiseadjacent in some implementations.

As used herein, directional and/or arbitrary terms, such as “top,”“bottom,” “front,” “back,” “left,” “right,” “up,” “down,” “upper,”“lower,” “inner,” “outer,” “internal,” “external,” “interior,”“exterior,” “proximal,” “distal” and the like can be used solely toindicate relative directions and/or orientations and may not otherwisebe intended to limit the scope of the disclosure, including thespecification, invention, and/or claims.

Where possible, like numbering of elements have been used in variousfigures. In addition, similar elements and/or elements having similarfunctions may be designated by similar numbering (e.g., element “10” andelement “210.”) Furthermore, alternative configurations of a particularelement may each include separate letters appended to the elementnumber. Accordingly, an appended letter can be used to designate analternative design, structure, function, implementation, and/orembodiment of an element or feature without an appended letter.Similarly, multiple instances of an element and or sub-elements of aparent element may each include separate letters appended to the elementnumber. In each case, the element label may be used without an appendedletter to generally refer to instances of the element or any one of thealternative elements. Element labels including an appended letter can beused to refer to a specific instance of the element or to distinguish ordraw attention to multiple uses of the element. However, element labelsincluding an appended letter are not meant to be limited to the specificand/or particular embodiment(s) in which they are illustrated. In otherwords, reference to a specific feature in relation to one embodimentshould not be construed as being limited to applications only withinsaid embodiment.

It will also be appreciated that where a range of values (e.g., lessthan, greater than, at least, and/or up to a certain value, and/orbetween two recited values) is disclosed or recited, any specific valueor range of values falling within the disclosed range of values islikewise disclosed and contemplated herein. Thus, disclosure of anillustrative measurement or distance less than or equal to about 10units or between 0 and 10 units includes, illustratively, a specificdisclosure of: (i) a measurement of 9 units, 5 units, 1 units, or anyother value between 0 and 10 units, including 0 units and/or 10 units;and/or (ii) a measurement between 9 units and 1 units, between 8 unitsand 2 units, between 6 units and 4 units, and/or any other range ofvalues between 0 and 10 units.

It is also noted that systems, methods, apparatus, devices, products,processes, compositions, and/or kits, etc., according to certainembodiments of the present invention may include, incorporate, orotherwise comprise properties, features, aspects, steps, components,members, and/or elements described in other embodiments disclosed and/ordescribed herein. Thus, reference to a specific feature, aspect, steps,component, member, element, etc. in relation to one embodiment shouldnot be construed as being limited to applications only within saidembodiment. In addition, reference to a specific benefit, advantage,problem, solution, method of use, etc. in relation to one embodimentshould not be construed as being limited to applications only withinsaid embodiment.

The headings used herein are for organizational purposes only and arenot meant to be used to limit the scope of the description or theclaims. To facilitate understanding, like reference numerals have beenused, where possible, to designate like elements common to the figures.

The present invention relates to systems and methods for mixing liquidfluids such as solutions or suspensions. The systems can be commonlyused as bioreactors or fermentors for culturing cells or microorganisms.By way of example and not by limitation, the inventive systems can beused in culturing bacteria, fungi, algae, plant cells, animal cells,protozoan, nematodes, and the like. The systems can accommodate cellsand microorganisms that are aerobic or anaerobic and are adherent ornon-adherent. The systems can also be used in association with theformation and/or treatment of solutions and/or suspensions that are forbiological purposes, such as media, buffers, or reagents. For example,the systems can be used in the formation of media where sparging is usedto control the pH of the media through adjustment of thecarbonate/bicarbonate levels with controlled gaseous levels of carbondioxide. The systems can also be used for mixing powders or othercomponents into a liquid where sparging is not required and/or where thesolution/suspension is not for biological purposes.

Depicted in FIG. 1 is one embodiment of an inventive mixing system 10incorporating features of the present invention. In general, mixingsystem 10 comprises a support housing 14, a container assembly 16 thatis supported within support housing 14, a drive motor assembly 15mounted on support housing 14 and a drive shaft 17 (FIG. 3) that extendsbetween drive motor assembly 15 and container assembly 16. Containerassembly 16 houses the liquid that is mixed and otherwise processed. Thevarious components of mixing system 10 will now be discussed in greaterdetail.

As depicted in FIG. 2, container assembly 16 comprises a container 18having a side 20 that extends from an upper end 22 to an opposing lowerend 24. Upper end 22 terminates at an upper end wall 33 while lower end24 terminates at a lower end wall 34. Container 18 also has an interiorsurface 26 that bounds a compartment 28. Compartment 28 is configured tohold a fluid. In the embodiment depicted, container 18 comprises aflexible, collapsible bag that is comprised of one or more sheets of aflexible, water impermeable polymeric film such as a low-densitypolyethylene. The polymeric film can have a thickness that is at leastor less than 0.02 mm, 0.05 mm, 0.1 mm, 0.2 mm, 0.5 mm, 1 mm, 2 mm, 3 mmor in a range between any two of the foregoing. Other thicknesses canalso be used. The film is sufficiently flexible that it can be rolledinto tube without plastic deformation and can be folded over an angle ofat least 90°, 180°, 270°, or 360° without plastic deformation.

The film can be comprised of a single ply material or can comprise twoor more layers which are either sealed together or separated to form adouble wall container. Where the layers are sealed together, thematerial can comprise a laminated or extruded material. The laminatedmaterial comprises two or more separately formed layers that aresubsequently secured together by an adhesive. One example of an extrudedmaterial that can be used in the present invention is the ThermoScientific CX3-9 film available from Thermo Fisher Scientific. TheThermo Scientific CX3-9 film is a three-layer, 9 mil cast film producedin a cGMP facility. The outer layer is a polyester elastomer coextrudedwith an ultra-low density polyethylene product contact layer. Anotherexample of an extruded material that can be used in the presentinvention is the Thermo Scientific CX5-14 cast film also available fromThermo Fisher Scientific. The Thermo Scientific CX5-14 cast filmcomprises a polyester elastomer outer layer, an ultra-low densitypolyethylene contact layer, and an EVOH barrier layer disposedtherebetween.

The material can be approved for direct contact with living cells and becapable of maintaining a solution sterile. In such an embodiment, thematerial can also be sterilizable such as by ionizing radiation.Examples of materials that can be used in different situations aredisclosed in U.S. Pat. No. 6,083,587 which issued on Jul. 4, 2000 andUnited States Patent Publication No. US 2003-0077466 A1, published Apr.24, 2003, which are hereby incorporated by specific reference.

In one embodiment, container 18 can comprise a two-dimensional pillowstyle bag. In another embodiment, container 18 can be formed from acontinuous tubular extrusion of polymeric material that is cut tolength. The ends can be seamed closed or panels can be sealed over theopen ends to form a three-dimensional bag. Three-dimensional bags notonly have an annular side wall but also a two dimensional top end walland a two dimensional bottom end wall. Three dimensional containers cancomprise a plurality of discrete panels, typically three or more, andmore commonly four to six. Each panel is substantially identical andcomprises a portion of the side wall, top end wall, and bottom end wallof the container. Corresponding perimeter edges of each panel are seamedtogether. The seams are typically formed using methods known in the artsuch as heat energies, RF energies, sonics, or other sealing energies.

In alternative embodiments, the panels can be formed in a variety ofdifferent patterns. Further disclosure with regard to one method ofmanufacturing three-dimensional bags is disclosed in United StatesPatent Publication No. US 2002-0131654 A1, published Sep. 19, 2002,which is incorporated herein by specific reference in its entirety.

It is appreciated that container 18 can be manufactured to havevirtually any desired size, shape, and configuration. For example,compartment 28 of container 18 can have a volume of at least or lessthan 10 liters, 30 liters, 100 liters, 250 liters, 500 liters, 750liters, 1,000 liters, 1,500 liters, 3,000 liters, 5,000 liters, 10,000liters or in a range between any two of the foregoing. Other volumes canalso be used. Although container 18 can be any shape, in one embodimentcontainer 18 is specifically configured to be generally complementary tothe chamber on support housing 14 in which container 18 is received sothat container 18 is properly supported within the chamber.

Although in the above discussed embodiment container 18 is depicted as aflexible bag, in alternative embodiments it is appreciated thatcontainer 18 can comprise any form of collapsible container ordisposable container. Container 18 can also be transparent or opaque.

Continuing with FIG. 2, formed on container 18 are a plurality of ports30 at upper end 22 and a plurality of ports 31 at lower end 24. Each ofports 30, 31 communicate with compartment 28. Although only a few ports30, 31 are shown, it is appreciated that container 18 can be formed withany desired number of ports 30, 31 and that ports 30, 31 can be formedat any desired location on container 18. Ports 30, 31 can be the sameconfiguration or different configurations and can be used for a varietyof different purposes. For example, ports 30, 31 can be coupled withfluid lines for delivering media, cell cultures, and/or other componentsinto container 18 and withdrawing fluid from container 18. Ports 30, 31can also be used for delivering gas to container 18, such as through asparger, and withdrawing gas from container 18.

Ports 30, 31 can also be used for coupling probes and/or sensors tocontainer 18. For example, when container 18 is used as a bioreactor orfermentor for growing cells or microorganisms, ports 30, 31 can be usedfor coupling probes such as temperature probes, pH probes, dissolvedoxygen probes, and the like. Various optical sensors and other types ofsensors can also be attached to ports 30, 31. Examples of ports 30, 31and how various probes, sensors, and lines can be coupled thereto isdisclosed in United States Patent Publication No. 2006-0270036,published Nov. 30, 2006 and United States Patent Publication No.2006-0240546, published Oct. 26, 2006, which are incorporated herein byspecific reference in their entirety. Ports 30, 31 can also be used forcoupling container 18 to secondary containers, to condenser systems, andto other desired fittings.

Mounted on lower end wall 34 is a sparger 36 having a gas line 37coupled thereto. Sparger 36 is designed to deliver gas bubbles to theculture or other liquid within container 18 for oxygenating and/orregulating content of various gases within the culture/fluid. As needed,a second or more spargers can be mounted on lower end wall 34. Thespargers can be the same or different configurations. For example, onesparger can be designed to deliver small bubbles for oxygenating while asecond sparger can be designed to deliver larger bubbles for strippingCO₂ from the culture/fluid. In some forms of the invention, one of thespargers can be an open tube or a tube with a porous frit withrelatively large pores, while the other sparger can be a tube with aporous frit with relatively small pores. The sparger can also comprise aperforated or porous membrane that is mounted on the end of a port or onthe interior surface of lower end wall 34 so as to extend over a port.It is appreciated that spargers come in a variety of differentconfigurations and that any type of spargers can be used as desired oras appropriate for the expected culture volumes, cells, fluids and otherconditions. In some uses of mixing system 10, a sparger may not berequired and thus sparger 36 can be eliminated.

It is appreciated that the various gas lines, fluid lines, spraginglines, drain lines and/or the like can be coupled to container 18 at thetime of manufacture so that they can be sterilized concurrently withcontainer 18. Alternatively, the lines can be connected to container 18either prior to or after inserting container 18 into support housing 14.The lines can be connected to container 18 using commonly known asepticconnectors.

Container assembly 16 further comprises a mixing assembly 40. Asdepicted in FIG. 3, mixing assembly 40 comprises an elongated tubularconnector 42 having a rotational assembly 48 mounted at one end and amixing element 64 mounted on the opposing end. More specifically,tubular connector 42 has a first end 44 and an opposing second end 46with a passage 49 that extends therebetween. In one embodiment, tubularconnector 42 comprises a flexible tube such as a polymeric tube. In oneembodiment, the tube is sufficiently flexible that it can be bent alongits longitudinal axis over an angle of at least 90°, 180°, 270°, or 360°without plastic deformation.

Tubular connector 42 is typically made from, comprises or consists of asufficiently flexible material, such as an elastomeric material, so thattubular connector can withstand repeated bending and deformation withoutappreciable structural yield and can possess a durometer on the Shore OOscale that is typically less than 98 and often less than 60 or 30. Othervalues can also be used. Tubular connector 42 can be formed from apolymeric material such flexible PVC or other polymers having thedesired properties. In other embodiments, tubular connector 42 cancomprise a rigid tube or a combination of rigid and flexible tubes.

Rotational assembly 48 is mounted to first end 44 of tubular connector42. As depicted in FIG. 4, rotational assembly 48 comprises an outercasing 50 having an outwardly projecting annular sealing flange 52 andan outwardly projecting mounting flange 53. A tubular hub 54 isrotatably disposed within outer casing 50. One or more bearingassemblies 55 can be disposed between outer casing 50 and hub 54 topermit free and easy rotation of hub 54 relative to casing 50. Likewise,one or more seals 57 can be formed between outer casing 50 and hub 54 sothat during use an aseptic seal can be maintained between outer casing50 and hub 54.

Hub 54 has an interior surface 56 that bounds an opening 58 extendingtherethrough. As will be discussed below in greater detail, interiorsurface 56 includes an engaging portion 61 having a polygonal or othernon-circular transverse cross section so that a driver portion 180 ofdrive shaft 17 (FIG. 3) passing through opening 58 can engage engagingportion 61 and facilitate rotation of hub 54 by rotation of drive shaft17. Hub 54 can also comprise a tubular stem 60 projecting away fromouter casing 50. Returning to FIG. 3, hub 54 can couple with first end44 of tubular connector 42 by stem 60 being received within first end44. A pull tie, clamp, crimp or other fastener can then be used tofurther secure stem 60 to tubular connector 42 so that a liquid tightseal is formed therebetween. Other conventional connecting techniquescan also be used.

In one embodiment, mixing element 64 comprises an impeller 65 having acentral hub 66 with a plurality of blades 68 radially outwardlyprojecting therefrom. In the embodiment depicted, blades 68 areintegrally formed as a unitary structure with hub 66. In otherembodiments, blades 68 can be separately attached to hub 66. It isappreciated that a variety of different numbers and configurations ofblades 68 can be mounted on hub 66. Hub 66 has a first end 70 with ablind socket 72 formed thereat. Socket 72 typically has a noncirculartransverse cross section, such as polygonal, so that it can engage adriver portion 178 of drive shaft 17. Accordingly, as will be discussedbelow in greater detail, when driver portion 178 is received withinsocket 72, driver portion 178 engages with impeller 65 such thatrotation of drive shaft 17 facilities rotation of impeller 65.

Impeller 65 can be attached to connector 42 by inserting first end 70 ofhub 66 within connector 42 at second end 46. A pull tie, clamp, crimp,or other type of fastener can then be cinched around second end 46 ofconnector 42 so as to form a liquid tight sealed engagement betweenimpeller 65 and connector 42. In other embodiment, mixing element 64 cancomprise a stir bar, paddle, or other mixing element that when rotated,reciprocated, or otherwise moved by drive shaft 17 will mix the liquidwithin container 18.

Turning to FIG. 2, rotational assembly 48 is secured to container 18 sothat tubular connector 42 and mixing element 64 extend into or aredisposed within compartment 28 of container 18. Specifically, in thedepicted embodiment container 18 has an opening 74 at upper end 22.Sealing flange 52 of outer casing 50 is sealed around the perimeter edgebounding opening 74 so that hub 54 is aligned with opening 74. Tubularconnector 42 having mixing element 64 mounted on the end thereofprojects from hub 54 into compartment 28 of container 18. In thisconfiguration, outer casing 50 is fixed to container 18. Thus, hub 54,tubular connector 42 and impeller 65 can freely rotate relative to outercasing 50 and container 18. As a result of rotational assembly 48sealing opening 74, compartment 28 is sealed closed so that it can beused in processing sterile fluids.

As depicted in FIG. 3, mixing assembly 40 is used in conjunction withdrive shaft 17. In general drive shaft 17 comprises a head section 164and a shaft section 166 that can be integrally formed as a singlecontinuous member or can comprise a plurality of sections that arecoupled together such as by threaded connection or other techniques.Drive shaft 17 can be comprised of high strength polymers, ceramics,composites, metals, such as aluminum, stainless steel, or other metalalloys, or other materials. Shaft section 166 has a first end 168 and anopposing second end 170. Disposed at first end 168 is head section 164which comprises a frustoconical engaging portion 172 that terminates atan outwardly extending circular plate 174. Notches 176 are formed on aperimeter edge of circular plate 174 and are used for engaging driveshaft 17 with drive motor assembly 15 as will be discussed below.

Formed at second end 170 of drive shaft 17 is driver portion 178. Driverportion 178 has a non-circular transverse cross section so that it canfacilitate locking engagement within hub 66 of impeller 65 as discussedabove. In the embodiment depicted, driver portion 178 has a polygonaltransverse cross section. However, other non-circular shapes can also beused. Driver portion 180 is also formed on shaft section 166 at ortoward first end 168. Driver portion 180 also has a non-circulartransverse cross section and is positioned so that it can facilitatelocking engagement within engaging portion 61 (FIG. 4) of rotationalassembly 48 as discussed above.

During use, as will be discussed below in further detail, drive shaft 17is advanced down through hub 54 of rotational assembly 48, throughtubular connecter 42 and into hub 66 of impeller 65. As a result of theinterlocking engagement of driver portions 178 and 180 with hubs 66 and54, respectively, rotation of drive shaft 17 by drive motor assembly 15(FIG. 1) facilitates rotation of hub 54, tubular connecter 42 andimpeller 65 relative to outer casing 50 of rotational assembly 48 andcontainer 18. As a result of the rotation of impeller 65 or other mixingelement 64, liquid within container 18 is mixed.

In an alternative embodiment, drive shaft 17 can be formed from 2, 3, 4,5 or more sections that are selectively coupled together. Furthermore,different sections can be made of different materials. By forming driveshaft 17 from multiple sections, it is easy to form a shaft having adesired length by adding or removing sections. Furthermore, the modulardrive shaft 17 can be used in a room with a low ceiling height. Forexample, a first section of drive shaft 17 can be partially advanceddown through drive motor assembly 15. Additional sections can then beprogressively attached thereto as the sections are progressivelyadvanced down through drive motor assembly 15. Accordingly, the fulllength of drive shaft 17 need not be simultaneously raised above drivemotor assembly 15 for passing therethrough. Alternative embodiments ofdrive shafts that can be used in the present inventive system, includingexamples of how separate sections can be coupled together, are disclosedin U.S. Pat. No. 8,641,314 which issued on Feb. 4, 2014 and which isincorporated herein by specific reference.

It is appreciated that mixing assembly 40, drive shaft 17 and thediscrete components thereof can have a variety of differentconfigurations and can be made of a variety of different materials.Alternative embodiments of and further disclosure with respect to mixingassembly 40, drive shaft 17, and the components thereof are disclosed inU.S. Pat. No. 7,384,783, issued Jun. 10, 2008 and US Patent PublicationNo. 2011/0188928, published Aug. 4, 2011 which are incorporated hereinin their entirety by specific reference.

Returning to FIG. 1, support housing 14 has a substantially cylindricalsidewall 82 that extends between an upper end 84 and an opposing lowerend 86. Lower end 86 has a floor 88 mounted thereto. As a result,support housing 14 has an interior surface 90 that bounds a chamber 92.An annular flange 94 is formed at upper end 84 and bounds an accessopening 96 to chamber 92. As discussed above, chamber 92 is configuredto receive container assembly 16 so that container 18 is supportedtherein.

Although support housing 14 is shown as having a substantiallycylindrical configuration, in alternative embodiments support housing 14can have any desired shape capable of at least partially bounding acompartment. For example, sidewall 82 need not be cylindrical but canhave a variety of other transverse, cross sectional configurations suchas polygonal, elliptical, or irregular. Furthermore, it is appreciatedthat support housing 14 can be scaled to any desired size. For example,it is envisioned that support housing 14 can be sized so that chamber 92can hold a volume of less than 50 liters, more than 10,000 liters or anyof the other volumes or range of volumes as discussed above with regardto container 18. Support housing 14 is typically made of metal, such asstainless steel, but can also be made of other materials capable ofwithstanding the applied loads of the present invention.

While support housing 14 can have any desired dimensions, in oneembodiment support housing 14 can be elongated with a relatively smalldiameter. Specifically, when mixing system 10 is used as a fermentor, itis desirable to have a high mixing rate of the culture within container18 to maintain consistent oxygenation and nutrient content throughoutthe culture. The mixing efficiency is increased by support housing 14and corresponding container 18 having a relatively small diameter sothat the culture is maintained relatively close to impeller 65. Becausethe diameter is relatively small, to enable batch processing attraditional volumes, the height of support housing 14 and correspondingcontainer 18 can be long relative to the diameter. Having a relativelytall support housing 14 and corresponding container 18 also increasesthe resident time of the sparged gas bubbles within container 18,thereby increasing the mass transfer of the gas into the fluid. Again,this has increased importance where mixing system 10 is used as afermentor.

By way of example and not by limitation, chamber 92 of support housing14 can have a central longitudinal axis 98 that extends through floor 88and access opening 96. Chamber 92 can have a maximum transverse diameterD that is normal to axis 98 and a height H that that extends alonglongitudinal axis 98 between floor 88 and access opening 96. Chamber 92can be made with diameter D being between about 15 cm to about 225 cmand a corresponding height H being between about 35 cm to about 500 cm.The ratio of height H to diameter D to can be in a range between about 1to about 10 with about 1.2 to about 4 and about 1.6 to about 3.3 beingmore common. In some embodiments, the ratio can be at least, or lessthan 1.5, 2, 2.5, 3, 4, 5 or in a range between any two of theforegoing. Again, other dimensions and ratios can also be used dependingon the intended use for mixing system 10. It is appreciated that thediameters and heights as discussed above with regard to support housing14 are also applicable to the diameter and height of container 18 whenpositioned within support housing 14. In addition, by making supporthousings 14 elongated with a relatively small diameter, mixing system 10can be passed through normal or narrow doorways through whichtraditionally sized mixing system would not fit. As such, mixing systems10 can be used in a broader range of locations.

Extending through sidewall 82 of support housing 14 at lower end 86 isan opening 99. Opening 99 is designed to receive ports 31 and the tubeor fittings attached thereto. As previously mentioned, any number ofports 31 can be formed on container 18. In turn, as also previouslydiscussed, sensors, probes, fluid lines, and the like can be coupledwith ports 31 so as to communicate with compartment 28 of container 18.

In one embodiment of the present invention means are provided forregulating the temperature of the liquid that is contained withincontainer 18 when container 18 is disposed within support housing 14. Byway of example and not by limitation, sidewall 82 can be jacketed so asto bound one or more fluid channels that encircle sidewall 82 and thatcommunicate with an inlet port and an outlet port. A fluid, such aswater or propylene glycol, can be pumped into the fluid channel throughthe inlet port. The fluid then flows in a pattern around sidewall 82 andthen exits out through the outlet port.

By heating or otherwise controlling the temperature of the fluid that ispassed into the fluid channel, the temperature of support housing 14 canbe regulated which in turn regulates the temperature of the fluid withincontainer 18 when container 18 is disposed within support housing 14. Inan alternative embodiment, electrical heating elements can be mounted onor within support housing 14. The heat from the heating elements istransferred either directly or indirectly to container 18.Alternatively, other conventional means can also be used such as byapplying gas burners to support housing 14 or pumping the fluid out ofcontainer 18, heating the fluid and then pumping the fluid back intocontainer 18. When using container 18 as part of a bioreactor orfermentor, the means for heating can be used to heat the culture withincontainer 18 to a temperature in a range between about 30° C. to about40° C. Other temperatures can also be used.

Turning to FIG. 5, drive motor assembly 15 comprises a housing 110having a top surface 112 and an opposing bottom surface 114 with anopening 116 extending through housing 110 between surfaces 112 and 114.A tubular motor mount 118 is rotatably secured within opening 116 ofhousing 110 and bounds a passage 120 extending therethrough. As depictedin FIG. 6, the upper end of motor mount 118 terminates at an end face122 having a locking pin 124 outwardly projecting therefrom. A thread126 encircles motor mount 118 adjacent to end face 122. A drive motor128, as depicted in FIG. 10, is mounted to housing 110 and engages withmotor mount 118 so as to facilitate select rotation of motor mount 118relative to housing 110. Drive motor 128 typically comprises anelectrical motor. A belt, gear, linkage, drive shaft or any othermechanism can be used to transfer energy from drive motor 128 to motormount 118 to facilitate select rotation of motor mount 118. The rotationcan be continuous in one direction or reciprocating.

Drive shaft 17 is configured to pass through motor mount 118 and thusthrough housing 110. The upper end of passage 120 extending throughmotor mount 118 forms an engaging portion having a frustoconicalconfiguration that is complementary to frustoconical engaging portion172 (FIG. 3) of drive shaft 17. As a result, the two engaging portionscan be complementarily mated to facilitate contacting engagement betweenmotor mount 118 and drive shaft 17 when drive shaft 17 is passed throughmotor mount 118 as depicted in FIG. 6.

When drive shaft 17 is passed through motor mount 118, plate 174 restson or slightly above end face 122 of motor mount 118 so that locking pin124 is received within a notch 176 thereof. As a result, drive shaft 17is locked to motor mount 118 so that rotation of motor mount 118facilitates concurrent rotation of drive shaft 17. A cap 130 (FIG. 5)can be threaded onto the end of motor mount 118 to prevent drive shaft17 from disengaging from motor mount 118. In turn, a protective cover132 can be placed over cap 130 and secured to housing 110.

Turning to FIG. 7, disposed on bottom surface 114 of housing 110 ofdrive motor assembly 15 is a restrainer 136. Restrainer 136 has aU-shaped interior surface 138 that bounds a U-shaped receiving slot 140that passes through restrainer 136. Receiving slot 140 is aligned withpassage 120 extending through motor mount 118 so that drive shaft 17 canpass therethrough. A U-shaped catch slot 142 is recessed on interiorsurface 138 and extends along the length thereof. Receiving slot 140 isconfigured so that rotational assembly 48 (FIG. 3) can be laterally slidinto receiving slot 140 so that opening 58 passing through hub 54 isaligned with passage 120 extending through motor mount 118. Asrotational assembly 48 is laterally slid into receiving slot 140,mounting flange 53 of rotational assembly 48 is received within catchslot 142 so that rotational assembly 48 is retained within receivingslot 140.

A gate 144 is hingedly mounted to restrainer 136 and can be selectivelymoved between an open position and a closed position. In the openposition, as shown in FIG. 7, gate 144 is rotated away from receivingslot 140 so that rotational assembly 48 can be freely laterally slidinto or out of receiving slot 140. Once rotational assembly 48 isdisposed within receiving slot 140, gate 144 can be rotated to theclosed position where gate 144 spans across the lateral opening ofreceiving slot 140 and thereby locks rotational assembly 48 withinreceiving slot 140. A latch 146 and can engage and secure gate 144 inthe closed position.

Accordingly, to facilitate attachment of rotational assembly 48 tohousing 100, gate 144 is rotated to the open position and rotationalassembly 48 is horizontally or laterally slid into receiving slot 140 ofrestrainer 136 so that mounting flange 53 of rotational assembly 48 isreceived within catch slot 142. Rotational assembly 48 is advanced intoreceiving slot 140 so that opening 58 of rotational assembly 48 (FIG. 3)aligns with passage 120 extending through motor mount 118. In thisposition, gate 144 is moved to the closed position and secured in placeby latch 146 so that rotational assembly 48 is locked to drive motorassembly 15. Further discussion of drive motor assembly 15 and how itengages with drive shaft 17 and alternative designs of drive motorassembly 15 are discussed in US Patent Publication No. 2011/0188928which was previously incorporated herein by specific reference.

As depicted in FIG. 1, drive motor assembly 15 is secured to supporthousing 14 by a mount 190. Mount 190 has a first end 192 secured toflange 94 at a first location and an opposing second end 194 that issecured to flange 94 at a second location. The first and secondlocations are on opposing sides of access opening 96 so that mount 190spans across access opening 96. In other embodiments, flange 94 can beeliminated and the opposing ends of mount 190 can be secured directly toupper end 84 of support housing 14 or upper end 84 of sidewall 82.Furthermore, flange 94 need not completely encircle access opening 96but could comprise a U- or C-shaped section or two, three, or morespaced apart sections that are mounted on sidewall 82.

As depicted in FIGS. 8 and 9, mount 190 comprises a brace 200 having afirst side 202 and an opposing second side 204 which each extend betweena first end 206 and an opposing second end 208. In one embodiment, brace200 comprises a plate but other structures can also be used. Mount 190also comprises a first rail 210 and a spaced apart second rail 212 thatboth span across access opening 96 and connect to flange 94 on opposingsides thereof. Brace 200 is centrally connected to first rail 210 andsecond rail 212 and spans therebetween so that brace 200 is centrallysupported over access opening 96. Brace 200 can be disposed so as to bevertically oriented, i.e., sides 202 and 204 are disposed in planes thatare vertically orientated, or disposed at an angle that is less than+/−30°, 20°, or 10° relative to vertical. In this configuration, mount190 has an H-shaped configuration.

In one embodiment, first rail 210 and second rail 212 can each comprisea single, unitary continuous rail. In the depicted embodiment, however,first rail 210 comprises a first forward rail 214A and a first rear rail216A while second rail 212 comprises a second forward rail 214B and asecond rear rail 216B. First forward rail 214A has a first end 220Aconnected to flange 94 at a first location and an opposing second end222A that is connected to brace 200 and particularly to first side 202of brace 200. First forward rail 214A has a generally L-shapedconfiguration that includes a foot 224A located at first end 220A and aleg 226A extending from foot 224A and connecting to brace 200. Foot 224Ahas a longitudinal axis that typically upwardly projects at an angle ofat least 45°, 60°, 75°, or 90° relative to the horizontal while leg 226Ahas a longitudinal axis that typically projects horizontally or at anangle less than 30°, 20°, or 10° relative to the horizontal.

Similarly, first rear rail 216A has a first end 230A that is connectedto brace 200 and particularly to second side 204 of brace 200 and anopposing second end 232A connected to flange 94 at a second location.First rear rail 216A has a generally L-shaped configuration thatincludes a foot 234A located at second end 232A and a leg 236A extendingfrom foot 234A and connecting to brace 200. Foot 234A has a longitudinalaxis that typically upwardly projects at an angle of at least 45°, 60°,75°, or 90° relative to the horizontal while leg 236A has a longitudinalaxis that typically projects horizontally or at an angle less than 30°,20°, 10° relative to the horizontal. Based on the above, first rail 210can be described as being a substantially U or arched shaped member thatextends between first end 220A and an opposing second end 232A havingfeet 224A and 234A disposed at the opposing ends and a single legextending therebetween. Again, the feet and leg can extend as discussedabove. Where first rail 210 is integrally formed a single, continuousmember, brace 200 can attach thereto such as by welding, or through theuse of fasteners, either directly or through the use of a bracket. Othertechniques can also be used.

Second forward rail 214B and second rear rail 216B have the sameconfigurations and alternatives as first forward rail 214A and firstrear rail 216A, respectively, as discussed above. As such, likereference elements between rails 214A and 214B and between rails 216Aand 216B are identified by like reference characters except that all ofthe elements of rails 214B and 216B are identified by a letter “B”rather than the letter “A”. Accordingly, second rail 212 can also bedescribed as being a substantially U or arched shaped member thatextends between first end 220B and an opposing second end 232B havingfeet 224B and 234B disposed at the opposing ends and a single legextending therebetween. Again, the feet and leg can extend as discussedabove. Where second rail 212 is integrally formed a single, continuousmember, brace 200 can attach thereto such as by welding, or through theuse of fasteners, either directly or through the use of a bracket. Othertechniques can also be used. In this configuration, mount 190, rails210, 212 and or brace 200 can project vertically above flange 94 orsupport housing 14 by as distance of at least 10 cm, 20 cm, 30 cm, 40,cm, 50 cm or more. This vertical spacing enables all or at least part ofdive motor assembly 15 to be retained outside of compartment 28 ofcontainer 18.

Extending between first end 220A of first rail 210 and first end 220B ofsecond rail 212 is a first mounting brace 240 while extending betweensecond end 232A of first rail 210 and second end 232B of second rail 212is a second mounting brace 242. Mounting braces 240 and 242 are used toremovably secure mount 190 to support housing 14. For example, fasteners244, such as screws, bolts, pins, or the like are shown removablycoupling first mounting brace 240 to flange 94. In contrast, clamps 246are shown removably coupling second mounting brace 242 to flange 94. Inone embodiment of the present invention, means are provided forremovably securing mount 190 to support housing 14. Fasteners 244 andclamps 246 are examples of such means. Other examples of means that canbe used include catches, latches, ties, couplings, and other types ofjoiners. In other embodiments, it is appreciated that mounting braces240 and 242 can be eliminated and the opposing ends of one or both ofrails 210 and 212 can be directly secured to flange 94 using one or moreof the above techniques.

As a result of mount 190 being removably attached to support housing 14,mixing system 10 become more modular. For example, support housing 14can be used with or without mount 190 and connected drive motor assembly15. Furthermore, mount 190 and connected drive motor assembly 15 can beeasily attached or retrofitted onto preexisting support housings 14. Inaddition, if drive motor assembly 15 needs to be repaired or replacedwith a different size, the combined mount 190 and drive motor assembly15 can be easily removed and repaired or replaced. Other benefits alsoexist. However, in other embodiments, it is also appreciated that mount190 could be permanently attached to flange 94, such as by welding.

In on embodiment of the present invention, drive motor assembly 15 issecured to mount 190 so that drive motor assembly 15 can be selectivelyraised and lowered between at least a first position and a secondposition. In addition, drive motor assembly 15 can be secured to mount190 so that drive motor assembly 15 is disposed at a first angularorientation when in the first position and is disposed at a secondangular orientation when in the second position, the second angularorientation being different from the first angular orientation. By wayof example and not by limitation, as depicted in FIG. 9, a four barlinkage system 250 used in association with a drive assembly 252 can beused to movably secure drive motor assembly 15 to mount 190.

As depicted in FIG. 10, linkage system 250 comprises a first lower arm254A and a first upper arm 256A that are disposed on a first side ofdrive motor assembly 15 and a second lower arm 254B and second upper arm256B that are disposed on an opposing second side of drive motorassembly 15. First lower arm 254A is elongated and extends between afirst end 258A and an opposing second end 260A. First upper arm 256A isalso elongated and extends between a first end 262A and an opposingsecond end 264A. Second lower arm 254B and second upper arm 256B aresubstantially the same configuration as first lower arm 254A and firstupper arm 256A, respectively, and thus like element between arms 254Aand 254B and between arms 256A and 256B are identified by like referencecharacters except that the elements for arms 254B and 256B areidentified with the letter “B”.

Housing 110 of drive motor assembly 15 has a first side face 270disposed on a first side of housing 110 and an opposing second side face272 disposed on an opposing second side of housing 110. A first lowerpivot pin 274A and a first upper pivot pin 276A project from first sideface 270 with pin 276A being disposed vertically above pin 274A. Acorresponding, second lower pivot pin 274B and second upper pivot pin276B (FIG. 11) also project from second side face 272 with pin 276Bbeing disposed vertically above pin 274B. In addition, as depicted inFIG. 10, a first lower pivot pin 280A and a first upper pivot pin 282Aare disposed on first end of 206 of brace 200, with pin 282A disposedabove pin 280A, and a second lower pivot pin 280B and a second upperpivot pin 282B are disposed on second end of 208 of brace 200, with pin282B disposed above pin 280B.

In the assembled state as depicted in FIGS. 11 and 12, first end 258A offirst lower arm 254A is hingedly attached to the first side of housing110 and, more particularly, first end 258A is rotatably attached tofirst side face 270 (FIG. 10) by being rotatably secured to first lowerpivot pin 274A or by being secured to first lower pivot pin 274A whichis rotatable relative to housing 110. Likewise, second end 260A of firstlower arm 254A is hingedly attached to first end 206 of brace 200 and,more particularly, second end 260A is rotatably attached to brace 200 bybeing rotatably secured to first lower pivot pin 280A or by beingsecured to first lower pivot pin 280A which is rotatable relative tobrace 200.

First end 258B of second lower arm 254B is hingedly attached to thesecond side of housing 110 and, more particularly, first end 258B isrotatably attached to second side face 272 by being rotatably secured tosecond lower pivot pin 274B or by being secured to second lower pivotpin 274B which is rotatable relative to housing 110. Likewise, secondend 260B of second lower arm 254B is hingedly attached to second end 208of brace 200 and, more particularly, second end 260B is rotatablyattached to brace 200 by being rotatably secured to second lower pivotpin 280B or by being secured to second lower pivot pin 280B which isrotatable relative to brace 200.

First end 262A of first upper arm 256A is hingedly attached to the firstside of housing 110 and, more particularly, first end 262A is rotatablyattached to first side face 270 by being rotatably secured to firstupper pivot pin 276A or by being secured to first upper pivot pin 276Awhich is rotatable relative to housing 110. Likewise, second end 264A offirst upper arm 256A is hingedly attached to first end 206 of brace 200and, more particularly, second end 264A is rotatably attached to brace200 by being rotatably secured to first upper pivot pin 282A or by beingsecured to first upper pivot pin 282A which is rotatable relative tobrace 200.

Finally, first end 262B of second upper arm 256B is hingedly attached tothe second side of housing 110 and, more particularly, first end 262B isrotatably attached to second side face 272 by being rotatably secured tosecond upper pivot pin 276B or by being secured to second upper pivotpin 276B which is rotatable relative to housing 110. Likewise, secondend 264B of second upper arm 256B is hingedly attached to second end 208of brace 200 and, more particularly, second end 264B is rotatablyattached to brace 200 by being rotatably secured to second upper pivotpin 282B or by being secured to second upper pivot pin 282B which isrotatable relative to brace 200.

In the above assembled configuration, drive motor assembly 15 can beselectively raised and lowered between at least two positions. Forexample, in FIG. 13 arms 254 and 256 are all pivoted to a loweredposition and thus drive motor assembly 15 is in a lowered position.However, in FIG. 14 arms 254 and 256 are upwardly pivoted to a raisedposition and thus drive motor assembly 15 is in a raised position whichis at an elevation higher than the lowered position. Thus, by pivotingarms 254 and 256 of four bar linkage system 250, drive motor assembly 15can be selectively raised and lowered between the raised position andthe lowered position and to any location therebetween.

Drive assembly 252 is used to control movement of four bar linkagesystem 250. In one embodiment, as depicted in FIG. 10, drive assembly252 comprises a piston 290. Piston 290 includes a piston rod 292 thatmoves within a cylinder 294. Piston 290 can comprise a pneumatic orhydraulic piston. As depicted in FIG. 9, piston rod 292 is hingedlycoupled to mount 190 or brace 200 thereof. More specifically, a stay 296is mounted to second side 204 of brace 200. An exposed first end ofpiston rod 292 is hingedly attached to stay 296 by a hinge 298. In turn,cylinder 294 is connected to linkage system 250. More specifically, asdepicted in FIG. 11, a support 300 is secured to and extends betweenfirst and second upper arms 256A and 256B. Cylinder 294 is hingedlyconnected to support 300 by a hinge 302.

Accordingly, drive assembly 252 can be selectively activated to lowerlinkage system 250 and thus move drive motor assembly 15 into thelowered position, as depicted in FIG. 13, or raise linkage system 250and thus move drive motor assembly 15 into the raised position, asdepicted in FIG. 14. More specifically, when drive assembly 252 isactivated to advance rod 292 out of cylinder 294, the arms of linkagesystem 250 are rotated downward and thus move drive motor assembly 15into the lowered position. In turn, when drive assembly 252 is activatedto retract rod 292 into cylinder 294, the arms of linkage system 250 arerotated upward and thus move drive motor assembly 15 into the raisedposition.

In an alternative embodiment, the orientation of piston 290 can bereversed so that cylinder 294 is connected to mount 190 and rod 292 isconnected to linkage system 250. It is appreciated that a variety ofother mechanical configurations can be used to raise and lower linkagesystem 250. For example, in other embodiments drive assembly 252 couldcomprise a gear assembly, pulley system, belt assembly or other movementsystem that is operated electrically, pneumatically, or hydraulically.Thus, drive assembly 252 can be selectively movable between an expandedand retracted position and have a first end coupled, such as hingedly,to mount 190 and have an opposing second end coupled, such as hingedly,to linkage system 250.

The vertical height by which drive motor assembly 15 (and also driveshaft 17 and mixing element 64 attached thereto) moves as it transfersbetween the lowered and raised position can vary based on factors suchas the length of the arms of linkage system 250. However, in oneembodiment, drive motor assembly 15, drive shaft 17, and or mixingelement 64 can move vertically by a distance of at least or less than 5cm, 10 cm, 20 cm, 40 cm, 60 cm or in a range between any two of theforegoing as drive motor assembly 15 is moved between the lowered andraised positions.

Furthermore, one of the benefits of using linkage system 250 to raiseand lower drive motor assembly 15 is that linkage system 250 can beconfigured to retain drive motor assembly 15 in the same angularorientation as it is moved between the lowered and raised positions orit can be configured to change the angular orientation of drive motorassembly 15 as it is moved between the lowered and raised positions. Forexample, as depicted in FIG. 13, a central longitudinal axis 306 ofpassage 120 of motor mount 118 (FIG. 7) is shown passing through housing110. Central longitudinal axis 306 is aligned with or extends parallelto the central longitudinal axis of drive shaft 17 (FIG. 3) when driveshaft 17 is passed down through passage 120. When drive motor assembly15 is in the lowered position shown in FIG. 13, and angle θ₁ is formedbetween axis 306 and the vertical. When drive motor assembly 15 is inthe raised position shown in FIG. 14, an angle θ₂ is formed between axis306 and the vertical. By modifying the configuration of linkage system250, such as by modifying the length and orientation of arms 254 and256, angle θ₂ can be the same as, larger than, or smaller than angle θ₁.For example, the difference between angle θ₁ and angle θ₂ can be atleast or less than 1°, 2°, 3°, 4°, 5°, 7°, 10°, 15°, 20° or in a rangebetween any two of the foregoing. The angle θ₁ and θ₂ can each be atleast or less than 1°, 3°, 5°, 7°, 10°, 15°, 20°, 25°, 30°, 35°, 40° orin a range between any two of the foregoing. The above angles andchanges in the angle or orientation are also application to drive shaft17 and mixing element 64 which are connected to drive motor assembly 15.

It can be desirable to change the angle orientation of drive motorassembly 15, drive shaft 17, and/or mixing element 64 to ensure thatmixing element 64 is retained in a desired position within container 18for optimal or desired mixing of the liquid therein as drive motorassembly 15, drive shaft 17, and/or mixing element 64 are raised andlowered. For example, when drive motor assembly 15 is in the loweredposition, shown in FIG. 13, mixing element 64 attached to drive shaft 17may be centrally positioned within container 18 for optimal mixing ofthe liquid therein. As drive motor assembly 15 is moved from the loweredposition to the raised position, shown in FIG. 14, the operation oflinkage system 250 causes drive motor assembly 15 to move forward, i.e.,toward sidewall 82 of support housing 14, as drive motor assembly 15 isbeing raised. As a result, drive shaft 17 and mixing element 64 are alsomoved forward. However, by concurrently changing the angular orientationof drive motor assembly 15, and thus also the angular orientation ofdrive shaft 17 and mixing element 64, mixing element 64 can be retainedcentrally within container 18 or otherwise moved to a desired lateralposition for optimal or desired mixing of the fluid at that desiredelevation.

One advantage of being able to selectively adjust the vertical heightand tilt or angular orientation of mixing element 64 and drive shaft 17through the use of linkage system 250 is that mixing system 10 can beused to maintain optimal mixing conditions of fluid within a singlecontainer assembly 16 over a relatively large change in fluid volumes.Specifically, the preferred position for mixing element 64 withincontainer 18 to achieve optimal mixing can be determined usingconventional techniques. This position can be measured as a height fromthe bottom of container assembly 16 and is subject to the height of thefluid within container assembly 16. Thus, as the fluid level increaseswithin container assembly 16, the height of the location for mixingelement 64 to achieve optimal mixing also increases and vice-a-versa.Maintaining mixing element 64 at the optimal location for mixing helpsto ensure that the fluid is homogeneous. This can be especially helpfulwhere mixing system 10 is functioning as a bioreactor or fermentor. Inthat case, the media, additives, and cells or microorganisms should becontinually turned over and homogeneously dispersed to ensure that allof the cells and microorganisms are being continuously and uniformly fedand oxygenated.

It is also common that the volume of fluid within container assembly 16will vary significantly. For example, when first starting a bioreactoror fermentor, the seed inoculum of cells or microorganisms can bedispersed into a rather small volume of media within container assembly16. As the cells/microorganisms grow and multiply, more media andadditives can be progressively added to container assembly 16. By usingthe inventive system, the seed inoculum can be delivered into arelatively large container assembly 16 although only a small volume ofmedia is initially being used. In this initial step, mixing element 64is lowered to achieve optimal mixing of the initial volume. As morefluid is progressively added into container 18, mixing element 64 isprogressively raised to maintain optimal mixing for the defined fluidvolume. When the culturing is complete or it is otherwise desired toremove the solution or suspension from container assembly 16, mixingelement 64 can again be progressively lowered as the fluid withincontainer assembly 16 is progressively lowered. During the mixingprocess, it is typically preferred to maintain a positive gas pressurewithin container assembly 16, such as in a range from 0.05 psi to about2 psi to keep container assembly 16 away from the moving mixing element64 and to keep container 18 against heated support housing 14 tomaintain temperature regulation. This can be more important during lowvolume processing.

The ability to progressively add and remove relatively large amounts ofliquid from a single container while maintaining optimal mixing of theliquid eliminates or at least decreases the need to transfer thesolution to different sized containers for processing. By using a singlecontainer for processing as opposed to moving the fluid betweendifferent sized containers, the inventive system decreases processingdown time, avoids the expense of unnecessary containers, minimizes therisk of contamination, and minimizes potential damage tocells/microorganisms. The inventive system can operate over a relativelyhigh turn-down ratio. A “turn-down ratio” is the ratio of maximum tominimum volumes of fluid that a single container can process whilemaintaining acceptable mixing conditions. For example, a turn-down ratioof 10:1 means that if the initial volume that a mixing system canprocess at acceptable mixing conditions is 10 liters, the volume offluid with the container can be increased by a factor of 10, i.e., up to100 liters, and the system would still be able to process the fluid atacceptable mixing conditions. By using inventive mixing system 10 as abioreactor, fermentor, or other system that requires mixing orsuspension it is appreciated that container assembly 16 can be sized tooperate with a turn-down ratio of at least 2:1, 3:1, 4:1, 5:1, 6:1, 8:1,10:1, 15:1, 20:1 or in a range between any two of the foregoing.

What constitutes acceptable mixing conditions is in part dependent uponwhat is being processed. When the system is functioning as a bioreactoror fermentor growing cells or microorganisms, the mixing should, ingeneral, assist in dispersal of the cells/microorganisms and sparged gasthroughout the solution so that the cells/microorganisms have access tothe required nutrients in the media and proper mass transfer is achievedwith the sparged gas. However, the mixing should not be so severe as toapply unwanted shear forces to the cells/microorganisms, createundesired splashing, or cause cavitation or a vortex in the solution,all of which can hamper the growth of cells/microorganisms.

Another advantage of one embodiment of the present invention is thatfour bar linkage system 250 automatically and concurrently adjusts thetilt or angular orientation of drive motor assembly 15, drive shaft 17and/or mixing element 64 so that mixing element 64 is at the optimal ordesired position for mixing liquid within container 18 as drive motorassembly 15, drive shaft 17 and/or mixing element 64 are moved betweenthe lowered and raised position. As such, no separate calculation oradjustment is required by the operator to ensure that mixing element 64is properly laterally positioned as mixing element is verticallyadjusted.

A method of assembly and use of mixing system 10 will now be discussed.During assembly, mixing assembly 40 is coupled with container 18 asdiscussed above. The assembly can then be sterilized, such as byradiation, so that compartment 28 and the components therein aresterile. To facilitate shipping and storage, container 18 can be foldedover at any location along the length of flexible tubular connector 42so as to minimize the length and size of container assembly 16. Duringuse, container assembly 16, including mixing assembly 40, is positionedwithin chamber 92 of support housing 14. Rotational assembly 48 is thenremovably connected to restrainer 136 of drive motor assembly 15 so thathub 54 is aligned with motor mount 118. Second end 170 of drive shaft 17is advanced down through motor mount 118, through hub 54 of rotationalassembly 48, through tubular connector 42 and finally into mixingelement 64.

In this position, drive shaft 17 is locked to motor mount 118 with firstdriver portion 180 engaging hub 54 and second driver portion 178engaging mixing element 64, as discussed above. As a result, rotation ofmotor mount 118 by drive motor 128 facilitates rotation of drive shaft17 which in turn facilitates the concurrent rotation of hub 54, tubularconnector 42, and mixing element 64. In turn, rotation of mixing element64 facilities mixing and suspension of the liquid within compartment 28of container 12.

A liquid, such as a cellular or microorganism culture, having a firstvolume can be disposed within compartment 28 of container 18. Mixingelement 64, which is disposed at a first location within compartment 28of container 18, can be moved, i.e., rotated, so as to mix the firstvolume of the liquid within compartment 28. Mixing element 64 can bemoved by drive motor assembly 15 rotating drive shaft 17 on which mixingelement 64 is attached. Liquid is added to compartment 28 of container18 so as to form a second volume of liquid within compartment 28. Fourbar linkage system 250 is used to raise mixing element 64 withincompartment 28 of container 18 to a second position. This can beaccomplished by four bar linkage system 250 raising drive motor assembly15 which in turn raises drive shaft 17 and mixing element 64 attachedthereto. Mixing element 64 is moved at the second position, such as bydrive motor assembly 15 rotating drive shaft 17, so as to mix the secondvolume of liquid within the container. Four bar linkage system 250 canalso simultaneously adjust the tilt or angular orientation of drivemotor assembly 15, drive shaft 17 and/or mixing element 64 as mixingelement 64 is raised from the first position to the second position sothat mixing element 64 is at the desired lateral position within thecontainer for mixing liquid at the second position.

In one embodiment, four bar linkage system 250 can be used to move thedrive motor assembly 15, drive shaft 17 and/or mixing element 64 to aplurality of different fixed elevations as the level of liquid withincontainer 18 changes, i.e., increases or decreases. For example, drivemotor assembly 15, drive shaft 17 and/or mixing element 64 could each bemoved to at least two, three, four, five, six or seven differentelevations. Likewise, drive motor assembly 15, drive shaft 17 and/ormixing element 64 can each be simultaneously moved to a different tiltor angular orientation as they are each moved to a different elevation.In another alternative embodiment, a sensor, such as an optical sensor,can be used to monitor the height of the liquid within container 18. Anelectronic controller, such as computer or computer processor, can beelectrically coupled with the sensor and four bar linkage system 250.The controller can then be used to automatically regulate the elevationand angular orientation of drive motor assembly 15, drive shaft 17and/or mixing element 64 based on detected changes in the level ofliquid within container 18.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed is:
 1. A liquid mixing system comprising: a supporthousing at least partially bounding a chamber, the support housinghaving a top opening that communicates with the chamber; a mount securedto the support housing; and a drive motor assembly secured to the mountso that the drive motor assembly can be selectively raised and loweredrelative to the support housing between a first position and a secondposition, the drive motor assembly pivoting about an axis of rotationthat raises or lowers as the drive motor assembly is moved between thefirst position and the second position, the drive motor assembly beingconfigured to engage a drive shaft for moving the drive shaft within thechamber of the support housing.
 2. The liquid mixing system as recitedin claim 1, further comprising a four bar linkage system that securesthe drive motor assembly to the mount, the four bar linkage system beingmovable to selectively raise and lower the drive motor assembly betweenthe first position and the second positions and to pivot the drive motorassembly about the axis of rotation.
 3. The liquid mixing system asrecited in claim 2, wherein the four bar linkage system is movablebetween a lowered position wherein the drive motor assembly is disposedat a first angular orientation relative to the axis of rotation and anelevated raised position wherein the drive motor assembly is disposed ata second angular orientation relative to the axis of rotation that isdifferent from the first angular orientation.
 4. The liquid mixingsystem as recited in claim 3, wherein the angular orientation of thedrive motor assembly automatically changes as the four bar linkagesystem is moved between the lowered position and the raised position. 5.The liquid mixing system as recited in claim 1, wherein the mountcomprises: an elongated first rail spanning across the top opening andhaving opposing ends secured to the support housing; an elongated secondrail spanning across the top opening and having opposing ends secured tothe support housing, the second rail being spaced apart from the firstrail; and a brace extending between the first rail and the second railso as to be disposed over the top opening.
 6. The liquid mixing systemas recited in claim 5, wherein the first rail and the second rail areU-shaped or arch shaped and upwardly project from the support housing.7. The liquid mixing system as recited in claim 2, further comprising adrive assembly that extends between the mount and the four bar linkagesystem and controls movement of the four bar linkage system.
 8. Theliquid mixing system as recited in claim 7, wherein the drive assemblycomprises a hydraulic or pneumatic piston.
 9. The liquid mixing systemas recited in claim 1, wherein the mount spans across the top opening.10. The liquid mixing system as recited in claim 1, further comprising:a flexible bag disposed within the chamber of the support housing, theflexible bag bounding a compartment; and a drive shaft coupled with thedrive motor assembly, at least a portion of the drive shaft beingdisposed within the compartment of the flexible bag, the drive motorassembly rotating the drive shaft when the drive motor assembly isactivated.
 11. The liquid mixing system as recited in claim 10, furthercomprising a mixing element disposed within the compartment of theflexible bag and coupled with the drive shaft.
 12. A liquid mixingsystem comprising: a mount; a drive motor assembly configured to engagea drive shaft for moving the drive shaft; and a four bar linkage systemextending between the mount and the drive motor assembly, the four barlinkage system being movable between a first position wherein the drivemotor assembly is disposed at a first location relative to the mount anda second position wherein the drive motor assembly is disposed at asecond location relative to the mount that is different from the firstlocation, the four bar linkage system comprising four separate arms eachhaving a first end hingedly connected to the drive motor assembly and anopposing second end hingedly connected to the mount.
 13. The liquidmixing system as recited in claim 12, wherein the four bar linkagesystem automatically changes an angular orientation of the drive motorassembly as the drive motor assembly is moved from the first location tothe second location.
 14. The liquid mixing system as recited in claim12, further comprising: a support extending between two of the four armsof the four bar linkage system; and a drive assembly extending betweenthe mount and the support.
 15. The liquid mixing system as recited inclaim 14, wherein the drive assembly comprises a hydraulic or pneumaticpiston.
 16. The liquid mixing system as recited in claim 12, furthercomprising a drive shaft coupled with the drive motor assembly and amixing element disposed on the drive shaft.
 17. A method for mixing aliquid, the method comprising: operating a drive motor assembly at afirst position so that the drive motor assembly rotates a drive shaftthat mixes a liquid within a compartment; raising the drive motorassembly vertically from the first position to a second position so thatthe drive motor assembly automatically pivots about an axis of rotationwhile the drive motor assembly is being raised from the first positionto the second position, the axis of rotation being raised vertically asthe drive motor assembly is moved from the first position to secondposition; and operating the drive motor assembly at the second positionso that the drive motor assembly rotates the drive shaft that mixes theliquid within the compartment.
 18. The method as recited in claim 17,wherein a mixing element is disposed on the drive shaft, the mixingelement vertically rising along a linear, vertical axis withincompartment as the drive motor assembly vertically rises from the firstposition to the second position.
 19. The method as recited in claim 17,wherein a four bar linkage system is used to raise the drive motorassembly from the first position to the second position.